Antiarrhythmic drugs are widely used in the management of rhythm disturbances as diverse as simple palpitations to recurrent ventricular fibrillation, the cause of the sudden cardiac death syndrome which kills half a million Americans per year. Response to this group of drugs is notoriously variable, with some patients experiencing clearcut benefit, while other, apparently similar individuals may develop new or worsening arrhythmias as a consequence of treatment. Moreover, response is often not static, but changes over time. The initial results of the Cardiac Arrhythmia Suppression Trial (CAST) highlight this problem: in CAST, drug therapy to suppress isolated ectopic beats after a myocardial infarction was associated with a 2-3-fold increase in mortality over the following year. This Program will test the central hypothesis that the effect of antiarrhythmic drugs is not static, but is determined by the changing intracellular and extracellular milieu in which drugs interact with target proteins in the heart. The effect of factors such as transmembrane potential, stimulation frequency, neurohormones, intracellular calcium and stretch on antiarrhythmic drug action will be studied by investigators with expertise in a wide range relevant fields, including ion channel physiology, the molecular biology of ion channels, control of intracellular calcium, modelling the biology of excitable tissues, and in assessment of drug action in vitro and in the intact heart. The central hypothesis will be tested in parallel studies in the intact heart, in myocytes, and in tissue culture lines and Xenopus oocytes expressing native or mutated mammalian (including human) ion channels. The programmatic approach will facilitate transfer of the results of hypothesis testing in one system to other systems. Moreover, because the Program brings together investigators with a wide range of skills, new strategies for the study of drug action and its modulation will be implemented. This Program will provide a basis for improved understanding of the acute and chronic modulation of ion channels and their block by drugs. In this way, more effective ways to use available agents and strategies for developing newer and safer compounds will be developed.